1. Field of the Invention
The present invention is broadly directed to a class of thiazolidinone and metathiazanone compounds and their derivatives useful as potassium channel inhibitors.
2. Description of Related Art
Potassium channels are expressed in eukaryotic and procaryotic cells, and are elements in the control of electrical and nonelectrical cellular functions. Subclasses of these channels have been named based on amino acid sequence and functional properties, and include for example voltage gated potassium channels (e.g., Kv1, Kv2, Kv3, Kv4). Subtypes within these subclasses have been characterized as to their putative function, pharmacology and distribution in cells and tissues (Chandy and Gutman, xe2x80x9cVoltage-gated potassium channel genesxe2x80x9d in Handbook of Receptors and Channels-Ligand and Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al., Curr. Opin. Neurobiol. 5:268, 1995).
Inhibitors of potassium channels lead to a decrease in potassium ion movement across cell membranes. Consequently, such inhibitors induce prolongation of the electrical action potential or membrane potential depolarization in cells containing the inhibited or blocked potassium channels. Prolonging of the electrical action potential is a preferred mechanism for treating certain diseases, e.g., cardiac arrhythmias (Colatsky et al., Circulation 82:2235, 1990). Membrane potential depolarization is a preferred mechanism for the treating of certain other diseases, such as those involving the immune system (Kaczorowski and Koo, Perspectives in Drug Discovery and Design, 2:233, 1994).
Potassium channels which exhibit functional, pharmacological and tissue distribution characteristics have been cloned. These cloned potassium channels are useful targets in assays for identifying candidate compounds for the treatment of various disease states. For example, the delayed rectifier voltage-gated potassium channel termed Ikur or Isus which has been reported to contain the Kv1.5 xcex1-subunit gene product is generally believed to be important in the repolarization of the human atrial action potential and thus is a candidate potassium channel target for the treatment of cardiac arrhythmias especially those occurring in the atria (Wang et al., Circ. Res. 73:1061, 1993; Fedida et al., Circ. Res. 73:210, 1993; Wang et al., J. Pharmacol Exp. Ther. 272:184, 1995; Amos et al., J. Physiol, 491:31, 1996).
The present invention is related to thiazolidinone and metathiazanone compounds which have been found to be useful as inhibitors of potassium channel function. Such compounds have been found to be especially active as inhibitors of voltage-gated potassium channels and may therefore be utilized for the treatment of diseases, conditions and disorders in which prolongation of cellular action potentials or the induction of cell membrane depolarization would be beneficial. These disease states, conditions and disorders include, but are not limited to cardiac arrhythmias, cell proliferative disorders including cancer, disorders of the auditory system, central nervous system mediated motor dysfunction and disorders of pulmonary, vascular and visceral smooth muscle contractility.
It is an object of the present invention, therefore, to provide a method of treating diseases, conditions and disorders in mammals, including humans, which respond to the inhibition of potassium channel function, which method comprises administering to a mammal in need thereof certain thiazolidinone or metathiazanone compounds.
Another object of the invention is to provide certain thiazolidinone and metathiazanone compounds which are useful for the treatment of such diseases, conditions and disorders in mammals, including humans.
This invention describes certain thiazolidinone and metathiazanone compounds and their utility as inhibitors of voltage-dependent potassium channel function, particularly potassium channels (i.e., IKur, Kv1.5) that could serve as targets for the treatment of cardiac arrhythmias especially those occurring in the atria (e.g., atrial flutter and atrial fibrillation) (Wang et al., Circ. Res. 73:1061, 1993; Fedida et al., Circ. Res. 73:210, 1993; Wang et al., J. Pharmacol. Exp. Ther. 272:184, 1995), as well as the potassium channels that could serve as targets for the treatment of immunologic diseases and conditions and disorders of the nervous system and the gastrointestinal system. Consequently, the present invention also provides a method for treating diseases, conditions and disorders which respond to the inhibition of potassium channel function such as cardiac arrhythmias and various immunologic, nervous and gatrointestinal diseases using certain thiazolidinone and metathiazanone compounds.
The invention is particularly based on the discovery that thiazolidinone and metathiazanone compounds of the following formula (I), and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, are inhibitors of potassium channel function. In particular, these thiazolidinone and metathiazanone compounds have demonstrated activity against the human potassium channels/currents IKur, Kv1.5. As a result, these compounds are useful in the treatment inter alia, of cardiac arrhythmias and other diseases, conditions and disorders.
Thus, in a first aspect, the present invention concerns a method for treating diseases, conditions and disorders which respond to the inhibition of potassium channel function by using a compound having the formula (I) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof: 
wherein,
v is 0 or 1;
t is 0, 1, or 2;
X in an orientation R1xe2x80x94Xxe2x80x94, is selected from xe2x80x94(CR42)pxe2x80x94; xe2x80x94(CR42)mO(CR4 2)nxe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)sxe2x80x94;xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)sxe2x80x94; xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94; 
xe2x80x94(CR42)mxe2x80x94NR4xe2x80x94(CR42)nxe2x80x94; 
xe2x80x83where p is an integer of 0 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 4; A is selected from an optionally substituted 3 to 7 membered carbocyclic ring and an optionally substituted 5 to 7 membered heterocyclic ring; each R4 is independently selected from H, a lower alkyl, an aryl and a heteroaryl; W is selected from O and NR5 where R5 is selected from H, lower alkyl, aryl, Cxe2x89xa1N and NHR4;
R1 is selected from H, an optionally substituted aryl and an optionally substituted heteroaryl;
Y, in an orientation R2xe2x80x94Yxe2x80x94, is selected from xe2x80x94(CR42)qxe2x80x94; xe2x80x94(CR42)mO(CR42)nxe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)mxe2x80x94; xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)mxe2x80x94; xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94 and a cycloalkyl, where q is an integer of 0 to 4 and m and n are as defined above;
R2 is selected from H, an optionally substituted aryl and an optionally substituted heteroaryl; and
R3 is selected from H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl and xe2x80x94NR6R7, where R6 is selected from H and optionally substituted lower alkyl; R7 is H, optionally substituted lower alkyl, optionally substituted aryl, xe2x80x94(SO2)R8, xe2x80x94COR8 and xe2x80x94C(O)NHxe2x80x94R4, R8 is selected from optionally substituted lower alkyl, optionally substituted aryl and optionally substituted heteroaryl or R6 and R7 together with the nitrogen to which they are attached form a heteroaryl.
When v is 1, formula (I) relates to a class of metathiazanone compounds of the following formula, with the various variables as defined above: 
When v is 0, formula (I) relates to a class of thiazolidinone compounds of the following formula, with the various variables as defined above: 
In a preferred aspect, the present invention concerns a method for treating diseases, conditions and disorders which respond to the inhibition of potassium channel function by using a compound having the formula (II) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof: 
wherein,
v is 0, or 1;
t is 0, 1, or 2;
X, in an orientation R1xe2x80x94Xxe2x80x94, is selected from xe2x80x94(CR42)pxe2x80x94; xe2x80x94(CR42)mO(CR42)nxe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)sxe2x80x94; xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)sxe2x80x94; and xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94; where p is an integer of 0 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 4; A is an optionally substituted 3 to 7 membered carbocyclic ring; each R4 is independently selected from H, a lower alkyl, an aryl and a heteroaryl;
R1 is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
Y, in an orientation R2xe2x80x94Yxe2x80x94, is selected from xe2x80x94(CR42)qxe2x80x94; xe2x80x94(CR42)mO(CR42)nxe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)mxe2x80x94; xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)mxe2x80x94;xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94and a cycloalkyl, where q is an integer of 0 to 4 and m and n are as defined above;
R2 is selected from H, an optionally substituted aryl and an optionally substituted heteroaryl; and
R3 is selected from H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl and xe2x80x94NR6R7, where R6 is selected from H and optionally substituted lower alkyl; R7 is H optionally substituted lower alkyl, optionally substituted aryl, xe2x80x94(SO2)R8, xe2x80x94COR8 and xe2x80x94C(O)NHxe2x80x94R4, R8 is selected from optionally substituted lower alkyl, optionally substituted aryl and optionally substituted heteroaryl or R6 and R7 together with the nitrogen to which they are attached form a heteroaryl.
More preferred is a method for treating diseases, conditions and disorders which respond to the inhibition of potassium channel function by using a compound having the formula (III) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof: 
wherein,
v is 0, or 1
t is 0, 1,or 2;
X, in an orientation R1xe2x80x94Xxe2x80x94, is selected from xe2x80x94(CR42)pxe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)sxe2x80x94; xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)sxe2x80x94; and xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94; where p is an integer of 0 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 3; A is an optionally substituted 3 to 7 membered carbocyclic ring; each R4 is independently selected from H, a lower alkyl, an aryl and a heteroaryl;
R1 is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R2 is an optionally substituted phenyl; and
R3 is selected from H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl and xe2x80x94NR6R7, where R6 is selected from H and optionally substituted lower alkyl; R7 is H, optionally substituted lower alkyl, optionally substituted aryl, xe2x80x94(SO2)R8, xe2x80x94COR8 and xe2x80x94C(O)NHxe2x80x94R4, R8 is selected from optionally substituted lower alkyl, optionally substituted aryl and optionally substituted heteroaryl or R6 and R7 together with the nitrogen to which they are attached form a heteroaryl.
In yet another aspect, the present invention is directed to certain compounds having the formula (IV) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof: 
wherein,
v is 0, or 1;
t is 0, 1, or 2;
X in an orientation R1xe2x80x94Xxe2x80x94, is selected from xe2x80x94(CR42)pxe2x80x94;xe2x80x94(CR423)(CH2)xe2x80x94; xe2x80x94(CR42)mO(CR42)nxe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)sxe2x80x94; xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)sxe2x80x94; xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94; 
xe2x80x94(CR42)mxe2x80x94NR4xe2x80x94(CR42)nxe2x80x94; 
xe2x80x83where p is an integer of 3 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 4; A is selected from an optionally substituted 3 to 7 membered carbocyclic ring and an optionally substituted 5 to 7 membered heterocyclic ring; each R4 is independently selected from H, a lower alkyl, an aryl and a heteroaryl; W is selected from O and NR5; R5 is selected from H, lower alkyl, aryl, Cxe2x89xa1N and NHR4;
R1 is selected from H an optionally substituted aryl and an optionally substituted heteroaryl;
R2 is selected from an optionally substituted aryl and an optionally substituted heteroaryl, with the provisos that (1) when X is xe2x80x94(CR42(CH2)xe2x80x94 and R4 is H then R1 cannot be a monoalkylamino or dialkylamino substituted alkoxy substituted phenyl; (2) when X is xe2x80x94(CR42)pxe2x80x94, R4 is H and p is 3 to 4 then R1 cannot be a monoalkylamino or dialkylamino substituted alkoxy substituted phenyl; (3) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R4 is H then R1 cannot be p-nitrophenyl, p-aminophenyl, (3-methoxy-4-ethoxyphenyl), or H and (4) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R1 is not H, then R2 cannot be pyridyl or indolyl.
In a preferred aspect, the present invention also concerns compounds having the formula (V) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof: 
wherein,
v is 0, or 1;
t is 0, 1, or 2;
X in an orientation R1xe2x80x94Xxe2x80x94, is selected from xe2x80x94(CR42)pxe2x80x94;xe2x80x94(CR42)(CH2)xe2x80x94; xe2x80x94(CR42)mO(CR42)nxe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)sxe2x80x94; xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)sxe2x80x94; and xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94; where p is an integer of 3 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 4; A is an optionally substituted 3 to 7 membered carbocyclic ring; each R4 is independently selected from H, a lower alkyl, an aryl and a heteroaryl;
R1 is selected from an optionally substituted aryl and an optionally substituted heteroaryl; and
R2 is selected from an optionally substituted aryl and an optionally substituted heteroaryl, with the provisos that (1) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R4 is H then R1 cannot be a monoalkylamino or dialkylamino substituted alkoxy substituted phenyl; (2) when X is xe2x80x94(CR42)pxe2x80x94, R4 is H and p is 3 to 4 then R1 cannot be a monoalkylamino or dialkylamino substituted alkoxy substituted phenyl; (3) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R4 is H then R1 cannot be p-nitrophenyl, p-aminophenyl, (3-methoxy-4-ethoxyphenyl), or H and (4) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R1 is not H, then R2 cannot be pyridyl or indolyl.
More preferred are compounds having the formula (VI) and pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, stereoisomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof: 
wherein,
v is 0, or 1;
t is 0, 1, or 2;
X, in an orientation R1xe2x80x94Xxe2x80x94, is selected from xe2x80x94(CR42)pxe2x80x94;xe2x80x94(CR42)(CH2)xe2x80x94; xe2x80x94(CR42)mCHxe2x95x90CH(CR42)sxe2x80x94; xe2x80x94(CR42)mCHxe2x89xa1CH(CR42)sxe2x80x94; and xe2x80x94(CR42)mxe2x80x94Axe2x80x94(CR42)mxe2x80x94; where p is an integer of 3 to 5, n is an integer of 2 to 4, m is an integer of 0 to 4 and s is an integer of 1 to 3; A is an optionally substituted 3 to 7 membered carbocyclic ring; each R4 is independently selected from H, a lower alkyl, an aryl and a heteroaryl;
R1 is selected from an optionally substituted aryl and an optionally substituted heteroaryl; and
R2 is an optionally substituted phenyl, with the provisos that (1) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R4 is H then R1 cannot be a monoalkylamino or dialkylamino substituted alkoxy substituted phenyl; (2) when X is xe2x80x94(CR42)pxe2x80x94, R4 is H and p is 3 to 4 then R1 cannot be a monoalkylamino or dialkylamino substituted alkoxy substituted phenyl; (3) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R4 is H then R1 cannot be p-nitrophenyl, p-aminophenyl, (3-methoxy-4-ethoxyphenyl), or H and (4) when X is xe2x80x94(CR42)(CH2)xe2x80x94 and R1 is not H, then R2 cannot be pyridyl or indolyl.
Preferred R1 substituents in formulae (I) through (VI) include phenyl; m- and p-methoxyphenyl; 3,4-methoxyphenyl; p-ethoxyphenyl; p-methylphenyl; p-ethylphenyl; 3,4-dimethylphenyl; 2,4-dichlorophenyl; p-chlorophenyl; p-bromophenyl; 3-bromo, 4-methoxyphenyl; indanyl and p-phenoxyphenyl. Preferred moieties for X in formulae (I) through (VI), in an orientation R1xe2x80x94Xxe2x80x94, include xe2x80x94CH2CH2xe2x80x94; xe2x80x94(CH2)3xe2x80x94; xe2x80x94(CH2)5xe2x80x94; xe2x80x94OCH2CH2xe2x80x94; xe2x80x94CHCH2CHxe2x80x94 (cyclopropyl); xe2x80x94CH2C(O)xe2x80x94; xe2x80x94CH2CHxe2x95x90CHxe2x80x94 and xe2x80x94CH2Cxe2x89xa1Cxe2x80x94. Preferred R2 substituents in formulae (I) through (VI) include phenyl; m-methylphenyl; 3-methyl, 4-methoxyphenyl; 3,4-dimethylphenyl; p-dimethylaminophenyl; m-methoxyphenyl, p-methoxyphenyl; naphthyl; 3,5-dimethylphenyl; p-(1-pyrrolidinyl)phenyl; 3,4-dichlorophenyl; benzodioxane; 3-bromo, 4-methoxyphenyl; 3,5-dimethoxylphenyl; 1,3-benzodioxol-5-yl; 3-(1-methyl indolyl); 2-quinolyl; 2-(5-ethyl thienyl); 2-(5-ethyl furyl); 2-(4,5-dimethyl furyl); 3,4-dimethoxylphenyl; p-methylthiophenyl; indanyl; naphthyl; p-ethylphenyl; p-isopropylphenyl; 2,3-dimethyl, 4-methoxyphenyl; o-methoxyphenyl; 2,5-dimethyl, 4-methoxyphenyl; 3,4dichlorophenyl; o-chlorophenyl; m-bromophenyl and 3-methylthio, 4-cyanophenyl. Preferred moieties for Y in formulae (I) and (II), in an orientation R2xe2x80x94Yxe2x80x94, include a simple covalent bond (i.e., xe2x80x94(CR42)q with q=0), xe2x80x94CH(C6H5)xe2x80x94; xe2x80x94CH2xe2x80x94; xe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH(CH3)xe2x80x94. Finally, the method, compound and compositions of the present invention are particularly directed to those instances involving formulae (I) through (VI) where v is 0 and t is 0.
The term xe2x80x9calkylxe2x80x9d as used alone or in combination herein refers to a straight or branched chain saturated hydrocarbon group containing from one to ten carbon atoms and the terms xe2x80x9cC1-6 alkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d refer to such groups containing from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. The term xe2x80x9coptionally substitutedxe2x80x9d when used in connection with an alkyl substituent refers to the replacement of up to two hydrogens, preferably on different carbon atoms with a radical selected form the group of lower alkoxy, phenyl, cyano, halo, trifluoromethyl, nitro, hydroxyl, alkanoyl, amino, monoalkyl amino and dialkylamino.
The term xe2x80x9calkoxyxe2x80x9d as used alone or in combination herein refers to a straight or branched chain alkyl group covalently bonded to the parent molecule through an xe2x80x94Oxe2x80x94 linkage containing from one to ten carbon atoms and the terms. xe2x80x9cC1-6 alkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d refer to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like. The term xe2x80x9coptionally substitutedxe2x80x9d when used in connection with an alkoxy substituent refers to the replacement of up to two hydrogens, preferably on different carbon atoms with a radical selected form the group of lower alkyl, phenyl, cyano, halo, trifluoromethyl, nitro, hydroxyl, alkanoyl, amino, monoalkyl amino and dialkylamino.
The term xe2x80x9calkoxyalkylxe2x80x9d refers to an alkyl group substituted with an alkoxy group.
The term xe2x80x9chaloalkylxe2x80x9d is a substituted alkyl, preferably a substituted lower alkyl, substituted with one or more halogen atoms, and preferably is a C1 to C4 alkyl substituted with one to three halogen atoms. One example of a haloalkyl is trifluoromethyl.
The term xe2x80x9calkanoylxe2x80x9d as used alone or in combination herein refers to an acyl radical derived from an alkanecarboxylic acid, particularly a lower alkanecarboxylic acid, and includes such examples as acetyl, propionyl, butyryl, valeryl, and 4-methylvaleryl.
The term xe2x80x9caminocarbonylxe2x80x9d means an amino-substituted carbonyl (carbamoyl or carboxamide) wherein the amino group can be a primary, secondary (mono-substituted amino) or tertiary amino (di-substituted amino) group preferably having as a substituent(s) a lower alkyl.
The term xe2x80x9ccarbocyclic ringxe2x80x9d refers to stable, saturated or partially unsaturated monocyclic ring hydrocarbyls of 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term xe2x80x9coptionally substitutedxe2x80x9d as it refers to xe2x80x9ccarbocyclic ringxe2x80x9d herein indicates that the carbocyclic ring may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups.
The term xe2x80x9ccarbocycloalkylxe2x80x9d refers to stable, saturated or partially unsaturated monocyclic, bridged monocyclic, bicyclic, and spiro ring hydrocarbyls of 3 to 15 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclohexyl, bicyclooctyl, bicyclononyl, spirononyl and spirodecyl. The term xe2x80x9coptionally substitutedxe2x80x9d as it refers to xe2x80x9ccarbocycloalkylxe2x80x9d herein indicates that the carbocycloalkyl group may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups.
The term xe2x80x9cheterocyclic ringxe2x80x9d as used herein refers to a stable, saturated, or partially unsaturated monocyclic ring system containing 5 to 7 ring members of carbon atoms and other atoms selected from nitrogen, sulfur and/or oxygen. Preferably, a heterocyclyl is a 5 or 6-membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen and/or sulfur. The term xe2x80x9coptionally substitutedxe2x80x9d as it refers to xe2x80x9cheterocyclic ringxe2x80x9d herein indicates that the heterocyclic ring may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups. Examples of such heterocyclic rings are isoxazolyl, imidazolinyl, thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, pyranyl, pyrazinyl, piperidyl, morpholinyl and triazolyl. The heterocyclic ring may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocyclyl that results in a stable structure.
The term xe2x80x9cheterocyclylxe2x80x9d as used herein refers to a stable, saturated, or partially unsaturated, monocyclic, bridged monocyclic, bicyclic, and spiro ring system containing carbon atoms and other atoms selected from nitrogen, sulfur and/or oxygen. Preferably, a heterocyclyl is a 5 or 6-membered monocyclic ring or an 8-11 membered bicyclic ring which consists of carbon atoms and contains one, two, or three heteroatoms selected from nitrogen, oxygen and/or sulfur. The term xe2x80x9coptionally substitutedxe2x80x9d as it refers to xe2x80x9cheterocyclylxe2x80x9d herein indicates that the heterocyclyl group may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups. Examples of such heterocyclyl groups are isoxazolyl, imidazolinyl, thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, pyranyl, pyrazinyl, piperidyl, morpholinyl and triazolyl. The heterocyclyl group may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocyclyl that results in a stable structure.
The term xe2x80x9cheteroarylxe2x80x9d as used herein refers to a stable, aromatic monocyclic or bicyclic ring system containing carbon atoms and other atoms selected from nitrogen, sulfur and/or oxygen. Preferably, a heteroaryl is a 5 or 6-membered monocyclic ring (optionally benzofused) or an 8-11 membered bicyclic ring which consists of carbon atoms and contains one, two, or three heteroatoms selected from nitrogen, oxygen and/or sulfur. The term xe2x80x9coptionally substitutedxe2x80x9d as it refers to xe2x80x9cheteroarylxe2x80x9d herein indicates that the heteroaryl group may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino, cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups. Examples of such heteroaryl groups are isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridyl, furyl, pyrimidinyl, pyrazolyl, pyridazinyl, furazanyl and thienyl. The heteroaryl group may be attached to the parent structure through a carbon atom or through any heteroatom of the heteroaryl that results in a stable structure.
The specific chemical nature of the optionally substituted heteroaryl groups for the terminal moieties R1 and R2 in the prior identified potassium channel inhibitor compounds is not narrowly critical and, as noted above, a wide variety of substituent groups are contemplated. Preferably, the substituents for the heteroaryl groups are selected such that the total number of carbon and hetero atoms comprising the substituted heteroaryls is no more than about 20.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d as used herein to identify substituent moieties, represent fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine.
The term xe2x80x9carylxe2x80x9d when used alone or in combination refers to an unsubstituted or optionally substituted monocyclic or bicyclic aromatic hydrocarbon ring system. Preferred are optionally substituted phenyl or naphthyl groups. The aryl group may optionally be substituted at one or more substitutable ring positions by one or more groups independently selected from optionally substituted alkyl (preferably an optionally substituted lower alkyl), optionally substituted alkoxy (preferably an optionally substituted lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups. Preferably, the aryl group is phenyl optionally substituted with up to four and usually with one or two groups, preferably selected from C1-6 alkyl, C1-6 alkoxy, as well as cyano, trifluoromethyl and halo. Two alkyl or two alkoxy substituents on a substituted phenyl may form a closed ring structure between the meta and para positions on the phenyl, thus forming an indanyl, benzodioxane, benzopyran and the like groups.
The term xe2x80x9caralkylxe2x80x9d alone or in combination refers to an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, and includes benzyl, and 2-phenylethyl.
The term xe2x80x9calkoxycarbonylxe2x80x9d alone or in combination means a radical of the formula xe2x80x94C(O)xe2x80x94alkoxy, in which alkoxy is as defined above.
The term xe2x80x9calkylcarbonyloxyxe2x80x9d alone or in combination means a radical of the formula xe2x80x94Oxe2x80x94C(O)-alkyl, in which alkyl is as defined above.
The term xe2x80x9calkenylxe2x80x9d means a two to seven carbon, straight or branched hydrocarbon containing one or more double bonds, preferably one or two double bonds. Examples of alkenyl include ethenylene, propenylene, 1,3-butadienyl, and 1,3,5-hexatrienyl.
Unless otherwise defined, the term xe2x80x9coptionally substitutedxe2x80x9d as used herein, refers to the substitution of a ring system at one or more positions with one or more groups selected from: C1-6 alkyl, C1-6 alkoxy, an optionally substituted phenyl, cyano, halo, trifluoromethyl, C1-8 alkoxycarbonyl, C1-6 alkyl carbonyloxy, mono- and bis-(C1-6 alkyl)-carboxamide, C1-6 alkyl amido, nitro, and mono- and bis-(C1-6 alkyl)-amino.
The term xe2x80x9ctreatingxe2x80x9d as used herein, describes the management and care of a patient afflicted with a condition, disease or disorder for which the administration of a compound in accordance with the present invention alters the action or activity of a potassium channel to prevent the onset of symptoms or complications associated with the condition, disease or disorder, to alleviate the symptoms or complications caused by the condition, disease or disorder, or to eliminate the condition, disease or disorder altogether.
Thiazolidinone and metathiazanone compounds of the previous formulae useful as potassium channel inhibitors in accordance with the present invention can be prepared in accordance with the following general procedure:
A mixture of an amine (1 equivalent), an aldehyde (2 equivalents), and a mercaptoacid (3 equivalents) in benzene or toluene is heated to a temperature in the range of 80xc2x0 C. to 100xc2x0. In some cases an amine hydrochloride can be used. In those instances, about 1-1.5 equivalents of NEt3 also are added. After 2-24 hr, the reaction mixture is allowed to cool to room temperature and the solvent can be removed under reduced pressure. The crude product is dissolved in EtOAc and washed with saturated NaHCO3, 1N HCl, and saturated NaCl. The organic layer is dried (Na2SO4), filtered and concentrated. Purification by column chromatography on silica gel gives the desired thiazolidinone or metathiazanone product. Oxidation of a thiazolidinone or a metathiazanone to the corresponding sulfoxide or sulfone is readily accomplished by treatment with meta-chloroperbenzoic acid at 0xc2x0 C.
It is recognized that there is at least one chiral center in the compounds used within the scope of the present invention and thus such compounds will exist as various stereoisomeric forms. Applicants intend to include all the various stereoisomers within the scope of the invention. Though the compounds may be prepared as racemates and can conveniently be used as such, individual enantiomers also can be isolated or preferentially synthesized by known techniques if desired. Such racemates and individual enantiomers and mixtures thereof are intended to be included within the scope of the present invention.
The present invention also encompasses the pharmaceutically acceptable salts, esters, amides, complexes, chelates, hydrates, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs of the compounds of formulae (I), (II), (III), (V), (V) and (VI). Pharmaceutically acceptable esters and amides can be prepared by reacting, respectively, a hydroxy or amino functional group with a pharmaceutically acceptable organic acid, such as identified below. A prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which is degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form. Generally, a prodrug has a different pharmakokinetic profile than the parent drug such that, for example, it is more easily absorbed across the mucosal epithelium, it has better salt formation or solubility and/or it has better systemic stability (e.g., an increased plasma half-life).
Those skilled in the art recognize that chemical modifications of a parent drug to yield a prodrug include: (1) terminal ester or amide derivatives which are susceptible to being cleaved by esterases or lipases; (2) terminal peptides which may be recognized by specific or nonspecific proteases; or (3) a derivative that causes the prodrug to accumulate at a site of action through membrane selection, and combinations of the above techniques. Conventional procedures for the selection and preparation of prodrug derivatives are described in H, Bundgaard, Design of Prodrugs, (1985). Those skilled in the art are well-versed in the preparation of prodrugs and are well-aware of its meaning.
As will be recognized by those skilled in the art, certain compounds used in accordance with the present invention can be used in their neat form or in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts of compounds of the present invention include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. These salts thus include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.
Also, any basic nitrogen-containing groups in compounds of the invention can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, omides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Water or oil soluble or dispersible products are thereby generally obtained.
The pharmaceutically acceptable salts of compounds used in accordance with the present invention also can exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, ethyl acetate and the like. Mixtures of such solvates also can be prepared. Such solvates are within the scope of the present invention.
The pharmacological profile of the potassium channel inhibitory activity of thiazolidinone and metathiazanone compounds falling within the teachings of the present invention can be readily assessed by those skilled in the art using routine experimentation, such as the procedures and techniques illustrated in the examples which follow. Assays for assessing the activity of particular compounds may employ cells stably transfected to express a specific potassium channel, as well as native mammalian cells. In particular, cells stably transfected to express a specific potassium channel, which have been treated with a voltage dependent fluorescent dye, such as bis-1,3-dibutylbarbituric acid)trimethine oxonol, can be used to gauge the inhibitory activity of potassium channel inhibitor compounds, possibly in comparison to known inhibitors. Alternatively, such cells can be primed with a detectible species, such as 86Rb, and then challenged with a particular compound, under conditions otherwise suitable for activating the potassium channel, to assess the potassium inhibitory activity of the compound. The potassium channel inhibitory activity of a compound also can be determined using isolated mammalian cells and the whole cell configuration of the known patch clamp technique (Hamill et al., Pflugers Archiv 391:85, 1981). These and other known techniques can be readily employed by those skilled in the art to assess the activity level of the potassium channel inhibitor compounds contemplated by the present invention.
Thiazolidinone and metathiazanone compounds suitable for use within the scope of the present invention may be administered by a variety of routes including orally, parenterally, sublingually, intranasally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intracardiac injection, or infusion techniques. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,2-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Thiazolidinone and metathiazanone compounds contemplated for use within the scope of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed as mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33, et seq.
To select preferred compounds from less preferred compounds, one uses by example the in vitro assays detailed under the sub-heading BioAssays hereafter. Typically, a preferred compound will produce half maximal blocking activity at a concentration ranging from about 10 nM to about 1 xcexcM in the in vitro assays described. One of ordinary skill will recognize that the final and optimum dose and regimen will be determined empirically for any given drug.
Total daily dose administered to a host in single or divided doses may be an amount, for example, from 0.001 to 100 mg of active ingredient per kg body weight on a daily basis and more usually 0.01 to 10 mg/kg/day. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. It is anticipated that a therapeutically effective serum concentration of active ingredient will be 10 nM to 10 xcexcM (5 ng/ml to 5 xcexcg/ml).
The amount of active ingredient that may be combined with carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the patient, the time of administration, the route of administration, the rate of excretion, whether a drug combination is used, and the severity of the particular disease.